2D and 3D Quantitative Structure‐Activity Relationship Studies on a Series of <i>bis‐</i>Pyridinium Compounds as Choline Kinase Inhibitors

Janardhan, Sridhara; Srivani, P.; Sastry, G. Narahari

doi:10.1002/qsar.200530199

Cited by 35 publications

(11 citation statements)

References 26 publications

(12 reference statements)

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“…A rigid biphenyl linker did yield the most potent compounds, and when paired with a 4-chloro- N -methylanilino substituent on the pyridinium moiety, gave rise to a number of promising agents [118]. Extensive molecular modeling of these compounds with the crystal structures of ChoKα have helped to highlight the importance of the linker moiety, distance between quaternary ammoniums, delocalization of positive charge by electron-donating groups, and steric hindrance [119]. …”

Section: Choline Kinase Inhibitionmentioning

confidence: 99%

Choline kinase alpha—Putting the ChoK-hold on tumor metabolism

Arlauckas

Popov

Delikatny

2016

Progress in Lipid Research

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It is well established that lipid metabolism is drastically altered during tumor development and response to therapy. Choline kinase alpha (ChoKα) is a key mediator of these changes, as it represents the first committed step in the Kennedy pathway of phosphatidylcholine biosynthesis and ChoKα expression is upregulated in many human cancers. ChoKα activity is associated with drug resistant, metastatic, and malignant phenotypes, and represents a robust biomarker and therapeutic target in cancer. Effective ChoKα inhibitors have been developed and have recently entered clinical trials. ChoKα's clinical relevance was, until recently, attributed solely to its production of second messenger intermediates of phospholipid synthesis. The recent discovery of a non-catalytic scaffolding function of ChoKα may link growth receptor signaling to lipid biogenesis and requires a reinterpretation of the design and validation of ChoKα inhibitors. Advances in positron emission tomography, magnetic resonance spectroscopy, and optical imaging methods now allow for a comprehensive understanding of ChoKα expression and activity in vivo. We will review the current understanding of ChoKα metabolism, its role in tumor biology and the development and validation of targeted therapies and companion diagnostics for this important regulatory enzyme. This comes at a critical time as ChoKα-targeting programs receive more clinical interest.

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Section: Choline Kinase Inhibitionmentioning

confidence: 99%

Choline kinase alpha—Putting the ChoK-hold on tumor metabolism

Arlauckas

Popov

Delikatny

2016

Progress in Lipid Research

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“…High levels of PtdCho resulting from an up-regulation of genes coding for Cho transporter and for CK correlate as a biochemical marker of breast cancer [19] while CKα depletion selectively kills many tumorderived cell lines [20][21][22]. Antitumoral strategy targeting this enzyme and rational drug design are currently actively investigated [23][24][25][26][27]. P. falciparum at the blood stage likely possesses two distinct proteins for the phosphorylation of Cho and Etn with specificity for their natural substrate in parasite lysates [28] and the recombinant PfCK (PlasmoDB: PF14_0020) has been characterized in vitro [29,30].…”

Section: Introductionmentioning

confidence: 99%

Comparison of the cellular and biochemical properties of Plasmodium falciparum choline and ethanolamine kinases

Alberge

Gannoun-Zaki

Bascunana³

et al. 2009

Biochemical Journal

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The proliferation of the malaria-causing parasite Plasmodium falciparum within the erythrocyte is concomitant with massive phosphatidylcholine and phosphatidylethanolamine biosynthesis. Based on pharmacological and genetic data, de novo biosynthesis pathways of both phospholipids appear to be essential for parasite survival. The present study characterizes PfCK (P. falciparum choline kinase) and PfEK (P. falciparum ethanolamine kinase), which catalyse the first enzymatic steps of these essential metabolic pathways. Recombinant PfCK and PfEK were expressed as His6-tagged fusion proteins from overexpressing Escherichia coli strains, then purified to homogeneity and characterized. Using murine polyclonal antibodies against recombinant kinases, PfCK and PfEK were shown to be localized within the parasite cytoplasm. Protein expression levels increased during erythrocytic development. PfCK and PfEK appeared to be specific to their respective substrates and followed Michaelis-Menten kinetics. The Km value of PfCK for choline was 135.3+/-15.5 microM. PfCK was also able to phosphorylate ethanolamine with a very low affinity. PfEK was found to be an ethanolamine-specific kinase (Km=475.7+/-80.2 microM for ethanolamine). The quaternary ammonium compound hemicholinium-3 and an ethanolamine analogue, 2-amino-1-butanol, selectively inhibited PfCK or PfEK. In contrast, the bis-thiazolium compound T3, which was designed as a choline analogue and is currently in clinical trials for antimalarial treatment, affected PfCK and PfEK activities similarly. Inhibition exerted by T3 was competitive for both PfCK and PfEK and correlated with the impairment of cellular phosphatidylcholine biosynthesis. Comparative analyses of sequences and structures for both kinase types gave insights into their specific inhibition profiles and into the dual capacity of T3 to inhibit both PfCK and PfEK.

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“…Such a result is also in accordance with the above result of 2D-QSAR. In addition, there is another red contour around O 26 , suggesting that if adding some substituents at proper sites makes the negative charges of O 26 increase (in virtue of the law of polarity alternation and the idea of polarity interference [42,43]), it may be possible to improve the activity. In addition, a large blue polyhedron exists at the end of the substituent R; it suggests that more negatively charged groups or atoms on the blue position will be disadvantageous to improving the biological activity.…”

Section: D-qsar Results and Discussionmentioning

confidence: 99%

A Combined 2D‐ and 3D‐QSAR Study on Analogues of ARC‐111 with Antitumor Activity

Liao

et al. 2008

QSAR Comb. Sci.

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Two-Dimensional (2D) and Three-Dimensional (3D) Quantitative Structure -Activity Relationships (QSARs) of a series of analogues of ARC-111 with antitumor activity expressed as pIC 50 , which is defined as the negative value of the logarithm of necessary molar concentration of these compounds to cause 50% growth inhibition against tumor cell lines P388, have been studied by using a combined method of the DFT, MM2, and statistics for 2D, as well as the Comparative Molecular Field Analysis (CoMFA) for 3D. The established 2D-QSAR model shows not only significant statistical quality, but also predictive ability, with the square of adjusted correlation coefficient R 2 A of 0.869 and the square of the crossvalidation coefficient q 2 of 0.834 as well as the square of predictive correlation coefficient R 2 pred of 0.867 for the test set. The 3D-QSAR model also shows good correlative and predictive capabilities in terms of R 2 (0.993) and q 2 (0.674) when CoMFA fields are used for the whole studied compounds. The results from 2D-and 3D-QSAR analyses conformably show that the steric interaction plays a crucial role in determining the cytotoxicity of the compounds and that selecting a moderate-size substituent R as well as increasing the negative charge of C 28 at the same time are advantageous to improving the antitumor activity. Such results might offer some useful theoretical references for understanding the action mechanism and directing the molecular design of this kind of compound with antitumor activity.

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2D and 3D Quantitative Structure‐Activity Relationship Studies on a Series of bis‐Pyridinium Compounds as Choline Kinase Inhibitors

Cited by 35 publications

References 26 publications

Choline kinase alpha—Putting the ChoK-hold on tumor metabolism

Choline kinase alpha—Putting the ChoK-hold on tumor metabolism

Comparison of the cellular and biochemical properties of Plasmodium falciparum choline and ethanolamine kinases

A Combined 2D‐ and 3D‐QSAR Study on Analogues of ARC‐111 with Antitumor Activity

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